Abstract
The formation of new blood vessels — known as angiogenesis — is essential for the growth and spread of solid tumours. It is promoted by the hypoxic conditions that develop in growing tumours and drive the expression of pro-angiogenic growth factors by tumour cells and various stromal cells. However, the tumour-associated vasculature (TAV) generated by angiogenesis is abnormal and is a key barrier to T cell entry into tumours. Moreover, the TAV creates a hostile microenvironment owing to an accumulation of suppressive immune cells, hypoxic and acidic conditions, and high interstitial pressure, which all limit the function and survival of effector T cells. Here, we present the mechanisms of T cell migration into tumours, including via high endothelial venules, and the importance of tertiary lymphoid structures, which function as privileged sites for antigen presentation, activation and co-stimulation of T cells, for mounting effective antitumour immunity. We describe how the tumour vasculature limits antitumour T cell responses and how T cell responses could be improved by therapeutic targeting of the TAV. In particular, the use of combination therapies that aim to normalize tumour blood vessels, favourably reprogramme endogenous immunity, and support T cell trafficking, function and persistence will be key to improving clinical responses.
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Acknowledgements
The authors thank the Ludwig Institute for Cancer Research, the University of Lausanne and the Lausanne University Hospital (CHUV), the Swiss National Science Foundation (SNSF# 310030_204326), the ISREC Foundation, the Fondazione Teofilo Rossi di Montelera e di Premuda, Cancera Foundation, and Biltema Foundation for their generous research support over the years. For this work, G.C. was funded by the Ludwig Institute for Cancer Research, as well as the CHUV and UNIL, and by generous grants from the Swiss National Science Foundation, Oncosuisse, the ISREC Foundation, Cancera Foundation, Mats Paulsson Foundation, and Biltema Foundation.
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The authors contributed to all aspects of the article. E.L. and M.I. contributed equally.
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G.C. has received honoraria from Bristol-Myers Squibb. The CHUV has received honoraria for advisory services provided by G.C. to Iovance and EVIR. G.C. has also has received royalties from the University of Pennsylvania for CAR T cell therapy licensed to Novartis and Tmunity Therapeutics, and royalties from the Ludwig Institute for Cancer Research, UNIL and CHUV for NeoTIL intellectual property previously licensed to Tigen Pharma. G.C. is inventor in technologies related to T cell expansion and engineering for T cell therapy. The other authors declare no competing interests.
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Lanitis, E., Irving, M. & Coukos, G. Tumour-associated vasculature in T cell homing and immunity: opportunities for cancer therapy. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01187-w
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DOI: https://doi.org/10.1038/s41577-025-01187-w
